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Reduction of Difluoromethylornithine-induced Thrombocytopenia in Rats with Ornithine while Maintaining Antitumor Activity¹

Departments of General Surgery [V. B. G., D. M. O., T-H. C., D. P., K. N.], Medical Oncology [J. A. A.], and Biochemistry and Molecular Biology [K. N.], The University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

The purpose of this study was to evaluate the effect of a concomitant infusion of ornithine on the difluoromethylornithine (DFMO)-induced thrombocytopenia and antitumor activity. Male Fischer 344 rats with either a transplantable fibrosarcoma or Ward colon tumor were given a 12-day continuous infusion of DFMO (2000 mg/kg/day) alone or with ornithine. The dose of ornithine was defined as the molar ratio to DFMO. A continuous infusion of DFMO significantly reduced circulating platelet counts to 5–16% of the control. Concomitant ornithine treatment at a molar ratio of 0.2–0.5 resulted in protection of the rat from thrombocytopenia while the antiproliferative activity of DFMO against the fibrosarcoma or Ward colon tumor was unaffected. At a higher ornithine:DFMO molar ratio (0.7), the DFMO-induced inhibition of tumor growth was blocked. Tissue polyamine levels suggest a different sensitivity of tumor and normal tissue to DFMO. Concomitant ornithine resulted in a greater increase in the polyamine levels of normal tissues, compared with the tumor. These results suggest that ornithine can selectively inhibit DFMO-induced thrombocytopenia while not affecting the antitumor activity.

¹ Supported by grants from Baxter Laboratories, Inc., and the National Cancer Institute (CA 34465).

² To whom requests for reprints should be addressed.

Received 4/25/88. Revised 10/31/88. Revised 4/17/89. Accepted 4/26/89.